In silico trial of baroreflex activation therapy for the treatment of obesity-induced hypertension

Clinical trials evaluating the efficacy of chronic electrical stimulation of the carotid baroreflex for the treatment of hypertension (HTN) are ongoing. However, the mechanisms by which this device lowers blood pressure (BP) are unclear, and it is uncertain which patients are most likely to receive clinical benefit. Mathematical modeling provides the ability to analyze complicated interrelated effects across multiple physiological systems. Our current model HumMod is a large physiological simulator that has been used previously to investigate mechanisms responsible for BP lowering during baroreflex activation therapy (BAT). First, we used HumMod to create a virtual population in which model parameters (n = 335) were randomly varied, resulting in unique models (n = 6092) that we define as a virtual population. This population was calibrated using data from hypertensive obese dogs (n = 6) subjected to BAT. The resultant calibrated virtual population (n = 60) was based on tuning model parameters to match the experimental population in 3 key variables: BP, glomerular filtration rate, and plasma renin activity, both before and after BAT. In the calibrated population, responses of these 3 key variables to chronic BAT were statistically similar to experimental findings. Moreover, blocking suppression of renal sympathetic nerve activity (RSNA) and/or increased secretion of atrial natriuretic peptide (ANP) during BAT markedly blunted the antihypertensive response in the virtual population. These data suggest that in obesity-mediated HTN, RSNA and ANP responses are key factors that contribute to BP lowering during BAT. This modeling approach may be of value in predicting BAT responses in future clinical studies.

Assessment of Sparus aurata (Gilthead Seabream) stock in Bardawil lagoon, southeast Mediterranean Sea

During present study period from October 2020 to April 2021, gilthead seabream Sparus aurata stock was estimated by using many assessment models to evaluate actual status on Bardawil lagoon. Length at first capture (Lc) was 17.10 and 16.70 cm for females and males respectively, but it was 16.9 cm for all individuals that corresponding age at first capture (tc= 2.49 year). Length at first recruit Lr was 10.70 and 9.70 cm for females and males, respectively, corresponding age tr= 0.77 year. The length at first maturity was Lm= 18.18 cm that corresponding age tm= 2.85 years. Virtual population analysis shows some of intensive capture on S. aurata at its early life’s. Yield per recruit and biomass per recruit tend to collapse as a result of high fishing mortalities. The current study concludes an exact overfishing pressure of S. aurata stock in Bardawil lagoon.

Quantitative Systems Pharmacology Modeling of Avadomide-Induced Neutropenia Enables Virtual Clinical Dose and Schedule Finding Studies

Avadomide is a cereblon E3 ligase modulator and a potent antitumor and immunomodulatory agent. Avadomide trials are challenged by neutropenia as a major adverse event and a dose-limiting toxicity. Intermittent dosing schedules supported by preclinical data provide a strategy to reduce frequency and severity of neutropenia; however, the identification of optimal dosing schedules remains a clinical challenge. Quantitative systems pharmacology (QSP) modeling offers opportunities for virtual screening of efficacy and toxicity levels produced by alternative dose and schedule regimens, thereby supporting decision-making in translational drug development. We formulated a QSP model to capture the mechanism of avadomide-induced neutropenia, which involves cereblon-mediated degradation of transcription factor Ikaros, resulting in a maturation block of the neutrophil lineage. The neutropenia model was integrated with avadomide-specific pharmacokinetic and pharmacodynamic models to capture dose-dependent effects. Additionally, we generated a disease-specific virtual patient population to represent the variability in patient characteristics and response to treatment observed for a diffuse large B-cell lymphoma trial cohort. Model utility was demonstrated by simulating the avadomide effect in the virtual population for various dosing schedules and determining the incidence of high-grade neutropenia, its duration, and the probability of recovery to low-grade neutropenia.

Efficient Closed Loop Simulation of Do-It-Yourself Artificial Pancreas Systems

Background: Numerical simulations, also referred to as in silico trials, are nowadays the first step toward approval of new artificial pancreas (AP) systems. One suitable tool to run such simulations is the UVA/Padova Type 1 Diabetes Metabolic Simulator (T1DMS). It was used by Toffanin et al. to provide data about safety and efficacy of AndroidAPS, one of the most wide-spread do-it-yourself AP systems. However, the setup suffered from slow simulation speed. The objective of this work is to speed up simulation by implementing the algorithm directly in MATLAB®/Simulink®. Method: Firstly, AndroidAPS is re-implemented in MATLAB® and verified. Then, the function is incorporated into T1DMS. To evaluate the new setup, a scenario covering 2 days in real time is run for 30 virtual patients. The results are compared to those presented in the literature. Results: Unit tests and integration tests proved the equivalence of the new implementation and the original AndroidAPS code. Simulation of the scenario required approximately 15 minutes, corresponding to a speed-up factor of roughly 1000 with respect to real time. The results closely resemble those presented by Toffanin et al. Discrepancies were to be expected because a different virtual population was considered. Also, some parameters could not be extracted from and harmonized with the original setup. Conclusions: The new implementation facilitates extensive in silico trials of AndroidAPS due to the significant reduction of runtime. This provides a cheap and fast means to test new versions of the algorithm before they are shared with the community.

Computational Eurotransplant kidney allocation simulations demonstrate the feasibility and benefit of T-cell epitope matching

The EuroTransplant Kidney Allocation System (ETKAS) aims at allocating organs to patients on the waiting list fairly whilst optimizing HLA match grades. ETKAS currently considers the number of HLA-A, -B, -DR mismatches. Evidently, epitope matching is biologically and clinically more relevant. We here executed ETKAS-based computer simulations to evaluate the impact of epitope matching on allocation and compared the strategies. A virtual population of 400,000 individuals was generated using the National Marrow Donor Program (NMDP) haplotype frequency dataset of 2011. Using this population, a waiting list of 10,400 patients was constructed and maintained during simulation, matching the 2015 Eurotransplant Annual Report characteristics. Unacceptable antigens were assigned randomly relative to their frequency using HLAMatchmaker. Over 22,600 kidneys were allocated in 10 years in triplicate using Markov Chain Monte Carlo simulations on 32-CPU-core cloud-computing instances. T-cell epitopes were calculated using the www.pirche.com portal. Waiting list effects were evaluated against ETKAS for five epitope matching scenarios. Baseline simulations of ETKAS slightly overestimated reported average HLA match grades. The best balanced scenario maintained prioritisation of HLA A-B-DR fully matched donors while replacing the HLA match grade by PIRCHE-II score and exchanging the HLA mismatch probability (MMP) by epitope MMP. This setup showed no considerable impact on kidney exchange rates and waiting time. PIRCHE-II scores improved, whereas the average HLA match grade diminishes slightly, yet leading to an improved estimated graft survival. We conclude that epitope-based matching in deceased donor kidney allocation is feasible while maintaining equal balances on the waiting list.